Florfenicol, 2,2-dichloro-N-((1R,2S)-3-fluoro-1-hydroxy-1-(4-(methylsulfonyl)phenyl)propan-2-yl)acetamide has the chemical structure

Florfenicol is a broad spectrum antibiotic with activity against many gram-negative and gram-positive bacteria, including utility in the prevention and treatment of bacterial infections due to susceptible pathogens in birds, reptiles, fish, shellfish and mammals. One of florfenicol's primary uses is in the treatment of pneumonia and associated respiratory infections in cattle (often referred to generally as Bovine Respiratory Disease or BRD) caused by Mannheimia haemolytica, Pasteurella multocida and/or Haemophilus somnus, also known as Histophilus somni. It is also indicated in the treatment of: pododermatitis in cattle caused by Fusobactrerium necrophorum and Bacteroides melaninogenicus; swine respiratory disease caused by Pasteurella multocida, Actinobacillus pleuropneumoniae, Streptococcus suis, Salmonella cholerasuis and/or Mycoplasma spp.; colibacillosis in chickens caused by Escherichia coli; enteric septicemia in catfish caused by Edwardsiella ictaluri; and furunculosis in salmon caused by Aeromnonas salmonicida. Other genera of bacteria that have exhibited susceptibility to florfenicol include Enterobacter, Klebsiella, Staphylococcus, Enterococcus, Bordetella, Proteus and Shigella. In particular, chloramphenicol-resistant strains of organisms, such as K. pneumoniae, E. cloacae, S. typhus and E. coli, are susceptible to florfenicol.
Florfenicol is most often administered to subjects either orally or parenterally, the latter being primarily intramuscular or intravenous. Due to its very low water solubility (approximately one mg/mL), organic solvents must be added to achieve the desired product concentration in a commercial formulation. Given the need for economical, single-dose treatment in the veterinary setting, there remains a need for new formulations of florfenicol at high concentrations. In addition, there is also a need for a form of florfenicol that is capable of maintaining effective plasma antibiotic levels for prolonged periods of time, in order to achieve improved economies in administration, e.g., to more readily provide single dose treatment, particularly in a veterinary setting. In addition there is a need for similar forms of florfenicol analogs.
One of the important applications is a treatment of bacterial infections by dosing the drug in drinking water given to animals. Such means of administration provides effective treatment of bacterial infection since florfenicol is reasonably well absorbed from the intestine and achieves necessary antibacterial systemic levels. However, as mentioned above, the aqueous solubility of florfenicol is quite limited; consequently the solubilization of florfenicol in water is slow. Achieving the desired concentrations in drinking water requires preparation of pre-dissolved florfenicol in form of a concentrate in a water-miscible organic solvent. Additionally, a water-soluble prodrug of florfenicol or of an analog of florfenicol that was easily dissolved directly in the drinking water for animals would be quite desirable.
The two other common phenicol antibiotics, chloramphenicol and thiamphenicol, contain two hydroxyl groups: one of a primary and one of a secondary alcohol type. A substantial amount of work has been carried out in producing water-soluble prodrugs of these two antibiotics by esterification of the more easily accessible primary alcohol rather than the hindered secondary alcohol group. Glycinates of these compounds have been extensively investigated. Some examples of such esters are disclosed in U.S. Pat. Nos. 3,740,411 and 3,770,889 (both of Akiyama et al.), British patent 1,263,116 of Sumitomo Chemical Co., and 3,405,165 and 3,475,470 (both of Rebstock et al.).
A much smaller amount of work has been carried out on the production of water-soluble prodrugs of florfenicol, which lacks a primary alcohol group. For instance, esters of florfenicol were described in U.S. Pat. No. 4,311,857 of Nagabhushan. This patent describes primarily aliphatic esters of florfenicol, and also discloses esters produced from several amino acids, particularly the glycinate, ornithate and lysinate esters. Such amino acid esters are also disclosed in U.S. Pat. No. 6,790,867 of Kohan et al. Murthy et al., U.S. published patent application 2005/014828, describes a number of esters of florfenicol with aliphatic carboxylic acids. Hecker et al., U.S. published patent application 2005/0182031, describes certain phosphate esters of florfenicol. However, there still remains a need for alternative forms of florfenicol that have additional beneficial features. (It should be noted that the citation of any reference herein should not be construed that such reference is available as “prior art” to the instant application.)